The Eph receptors represent the largest family of receptor tyrosine kinases. The Eph receptors and their ephrin ligands are widely expressed during development and in the adult organism, playing important roles in axon guidance, vasculogenesis and cell migration. Eph receptors are unique among other receptor kinases in that they fall into two subclasses with distinct ligand specificities, and in that they can also function as ligands activating bi-directional signaling. Understanding the mechanism of Eph/ephrin signaling requires a detailed structural and biophysical characterization of the Eph receptors, the ephrins, and their interactions with each other and with other regulatory proteins. The specific aims of our proposed investigations are: 1) Structural characterization of full Eph ectodomains alone and in complex with ephrins; 2) Structural characterization of the interactions of EphB2 with the NMDA Receptor and amyloid precursor protein derived A; 4) Production and structural characterization of functional full-length Eph receptors.